An unintended consequence of modernization is a dramatic increase in obesity and the prevalence of Metabolic Syndrome and Type 2 Diabetes (T2DM). Insulin resistance is a hallmark of these conditions. This proposal focuses on the pathogenesis of insulin resistance in skeletal muscle, as it comprises the majority of insulin sensitive tissue. High fat (HF) feeding results in insulin resistance and an increase in muscle extracellular matrix (ECM) collagen. Pharmacological or genetic manipulations that reverse or prevent the increase in ECM increases capillary density and corrects the insulin resistant state. The increase in collagen contributes to insulin resistance in skeletal muscle by binding to integrin receptors. Integrins are ubiquitously expressed dimers containing an ? (itg?) and ? (itg?) subunit. The effect of integrins depends on the specific integrin receptor and the cell typ that expresses it. A seminal finding is that the role of integrins is uniquely amplified in mice made insulin resistant by a HF diet. This key finding is likely due to the increased quantity of their ECM ligands. Insulin resistance occurs in both skeletal muscle and the vascular structures that perfuse it. Recent data suggests that insulin resistance at these sites is mediated by integrins. The hypothesis tested in the current proposal is that muscle insulin resistance in response to a HF diet occurs because ECM-Integrin interaction impedes insulin access to muscle through effects on endothelial cells and impairs insulin sensitivity by effects directly on muscle fibers. This hypothesis will be addressed in lean and HF-fed insulin resistant mice with muscle and endothelial inducible deletions of genes for the highly conserved proteins that are common to integrin receptors and their key cytosolic regulatory sites. Insulin action will be measured using the hyperinsulinemic, euglycemic clamp in the conscious mouse combined with isotopes to obtain an index of muscle glucose uptake. Indices of insulin access will be obtained by assessing conjugated-fluorescent insulin movement from the vessels, vascular reactivity, and angiogenesis. Muscle glucose uptake and metabolism will be assessed in vivo and in vitro. Experiments in Specific Aim 1 are designed to test whether integrins and the IPP contribute to muscle insulin resistance by impeding insulin access to muscle of HF-fed mice. Experiments in Specific Aim 2 will test whether integrins and the IPP contribute to muscle insulin resistance by impairing insulin sensitivity directly on the muscle itself in HF-fed mice. The experiments proposed herein will define the means by which the integrin system couples ECM remodeling to the pathology of insulin resistance and identify potential therapeutic targets for treatment of insulin resistance, Metabolic Syndrome and T2DM.